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PubMed2000

Spatial distribution and characteristics of voltage-gated calcium signals within visual interneurons.

Most of our knowledge about insect calcium currents is derived from studies on cultured or dissociated somata. So far, only little data on calcium currents are available for neurons including their dendritic and presynaptic structures. Here we combined the switched-electrode voltage-clamp technique with optical recording using calcium-sensitive dyes in identified fly visual interneurons in vivo to characterize the voltage dependence and dynamics of calcium currents quantitatively and in a spatially resolved way. For all three cell types considered, i.e., centrifugal horizontal (CH), horizontal system (HS), and vertical system (VS) cells, the activation curve is rather flat and covers a voltage range from -60 to -20 mV in dendritic as well as presynaptic areas of the cells. The calcium increase is fastest for CH cells with a time constant of approximately 70 ms. In HS and VS cells, the time constant amounts to 400-700 ms. The calcium dynamics as determined in different regions of the cells are similar except for a small segment between the axon and the dendrite in HS and VS cells, where the calcium increase is significantly faster. In summary, the results show the existence of a low-voltage-activated calcium current with little or no inactivation in dendritic as well as presynaptic regions of fly lobula plate tangential cells.

Animals↗
PubMed2006

Modulation of calcium signalling by dominant negative splice variant of ryanodine receptor subtype 3 in native smooth muscle cells.

The ryanodine receptor subtype 3 (RYR3) is expressed ubiquitously but its physiological function varies from cell to cell. Here, we investigated the role of a dominant negative RYR3 isoform in Ca2+ signalling in native smooth muscle cells. We used intranuclear injection of antisense oligonucleotides to specifically inhibit endogenous RYR3 isoform expression. In mouse duodenum myocytes expressing RYR2 subtype and both spliced and non-spliced RYR3 isoforms, RYR2 and non-spliced RYR3 were activated by caffeine whereas the spliced RYR3 was not. Only RYR2 was responsible for the Ca2+-induced Ca2+ release mechanism that amplified Ca2+ influx- or inositol 1,4,5-trisphosphate-induced Ca2+ signals. However, the spliced RYR3 negatively regulated RYR2 leading to the decrease of amplitude and upstroke velocity of Ca2+ signals. Immunostaining in injected cells showed that the spliced RYR3 was principally expressed near the plasma membrane whilst the non-spliced isoform was revealed around the nucleus. This study shows for the first time that the short isoform of RYR3 controls Ca2+ release through RYR2 in native smooth muscle cells.

Alternative Splicing↗
PubMed2001

Calcium signalling: IP3 rises again...and again.

Recent results indicate that 'regulators of G-protein signalling' may contribute to the generation of receptor-specific patterns of cytosolic Ca2+ oscillations by associating with specific receptors, accelerating G-protein inactivation and responding to changes in cytosolic Ca2+.

Animals↗
PubMed2006

Calcium signals are affected by ciprofloxacin as a consequence of reduction of mitochondrial DNA content in Jurkat cells.

The effects of ciprofloxacin on mitochondrial DNA (mtDNA) content, oxygen consumption, mitochondrial membrane potential, cellular ATP formation, and capacitative Ca(2+) entry into Jurkat cells were investigated. In cells incubated for several days with 25 mug/ml ciprofloxacin, a 60% reduction of mtDNA content, inhibition of the respiratory chain, and a significant decrease in mitochondrial membrane potential were observed. These changes led to a decrease in the calcium buffering capacity of mitochondria which, in turn, resulted in a gradual inhibition of the capacitative Ca(2+) entry. On days 4, 7, and 11 of incubation with ciprofloxacin, the initial rates of Ca(2+) entry were reduced by 33%, 50%, and 50%, respectively. Ciprofloxacin caused a transient decrease in the cellular capability for ATP formation. In cells incubated for 15 min with glucose, pyruvate, and glutamine as exogenous fuel, ciprofloxacin reduced ATP content by 16% and 35% on days 4 and 7, respectively, of incubation with the drug. However, on day 11 of incubation with ciprofloxacin, a recovery of cellular ATP formation was observed. In conclusion, long-term exposure of Jurkat cells to ciprofloxacin at a concentration of 25 mug/ml seriously affects cellular energy metabolism and calcium homeostasis.

Adenosine Triphosphate↗
PubMed2002

Dual action of estrogen on glutamate-induced calcium signaling: mechanisms requiring interaction between estrogen receptors and src/mitogen activated protein kinase pathway.

Conjugated equine estrogens (CEE) is the most widely prescribed pharmaceutical estrogen replacement therapy (ERT) for postmenopausal women in the United States and is the ERT of the Women's Health Initiative. Previous studies from our laboratory have demonstrated that CEE exerts neurotrophic and neuroprotective effects in neurons involved in learning and memory, and which are affected in Alzheimer's disease. The present work demonstrates that CEE potentiated the rise in intracellular calcium ([Ca(2+)](i)) following exposure to physiological concentrations of glutamate. In contrast, the reverse effect occurred in the presence of excitotoxic levels of glutamate exposure, where CEE attenuated the rise in [Ca(2+)](i). Potentiation of the glutamate response was mediated by the NMDA receptor, as the NMDA receptor antagonist MK-801 blocked the CEE-induced potentiation, whereas the L-type calcium channel blocker nifedipine did not. Further, the CEE-potentiated glutamate response was mediated by a src tyrosine kinase, as the tyrosine kinase inhibitor PP2 blocked the potentiation induced by CEE and neurons treated with CEE displayed increased phosphorylated tyrosine. The inhibition by CEE of [Ca(2+)](i) rise in the presence of excitotoxic levels of glutamate was mediated by mitogen activated protein kinase (MAPK), as the protective effect of CEE was blocked by inhibiting MAPK activation with PD98059. These data provide potential mechanisms to explain the cognitive enhancing and neuroprotective effects exerted by ERT.

Animals↗
PubMed2003

Calcium signaling: NAADP ascends as a new messenger.

NAADP is now established as a Ca(2+) messenger by recent studies which have shown that it is active in various cells, identified the targeted Ca(2+) stores and demonstrated a stimulus-activated increase in its endogenous levels.

Animals↗
PubMed2005

Taurine replacement attenuates hyperalgesia and abnormal calcium signaling in sensory neurons of STZ-D rats.

The etiology of painful diabetic neuropathy is poorly understood, but may result from neuronal hyperexcitability secondary to alterations of Ca2+ signaling in sensory neurons. The naturally occurring amino acid taurine functions as an osmolyte, antioxidant, Ca2+ modulator, inhibitory neurotransmitter, and analgesic such that its depletion in diabetes may predispose one to neuronal hyperexcitability and pain. This study reports the effects of taurine replacement on hyperalgesia and sensory neuron Ca2+ homeostasis in streptozotocin-diabetic (STZ-D) rats. Nondiabetic and STZ-D rats were treated with a 2% taurine-supplemented diet for 6-12 wk. Thermal hyperalgesia and mechanical allodynia were determined by measuring hindpaw withdrawal latency to radiant heat and the withdrawal threshold to the von Frey anesthesiometer. Intracellular Ca2+ signaling was explored in neurons from L4-L6 dorsal root ganglia (DRG), using fura 2 fluorescence. Taurine replacement of diabetic rats attenuated deficits of nerve conduction and prevented reductions of mechanical and thermal withdrawal threshold and latency, respectively. In small DRG sensory neurons from diabetic rats, recovery of intracellular Ca2+ concentration ([Ca2+]i) in response to KCl was slowed and 73% corrected by taurine. The amplitudes of caffeine and ATP-induced [Ca2+]i transients were decreased by 47 and 27% (P < 0.05), respectively, in diabetic rat DRG sensory neurons and corrected by 74 and 93% (P < 0.05), respectively, by taurine replacement. These data indicate that taurine is important in the regulation of neuronal Ca2+ signaling and that taurine deficiency may predispose one to nerve hyperexcitability and pain, complicating diabetes.

Adenosine Triphosphate↗
PubMed2005

Olfactory nerve stimulation-induced calcium signaling in the mitral cell distal dendritic tuft.

Olfactory receptor neuron axons form the olfactory nerve (ON) and project to the glomerular layer of the olfactory bulb, where they form excitatory synapses with terminal arborizations of the mitral cell (MC) tufted primary dendrite. Clusters of MC dendritic tufts define olfactory glomeruli, where they involve in complex synaptic interactions. The computational function of these cellular interactions is not clear. We used patch-clamp electrophysiology combined with whole field or two-photon Ca2+ imaging to study ON stimulation-induced Ca2+ signaling at the level of individual terminal branches of the MC primary dendrite in mice. ON-evoked subthreshold excitatory postsnaptic potentials induced Ca2+ transients in the MC tuft dendrites that were spatially inhomogeneous, exhibiting discrete "hot spots." In contrast, Ca2+ transients induced by backpropagating action potentials occurred throughout the dendritic tuft, being larger in the thin terminal dendrites than in the base of the tuft. Single ON stimulation-induced Ca2+ transients were depressed by the NMDA receptor antagonist D-aminophosphonovaleric acid (D-APV), increased with increasing stimulation intensity, and typically showed a prolonged rising phase. The synaptically induced Ca2+ signals reflect, at least in part, dendrodendritic interactions that support intraglomerular coupling of MCs and generation of an output that is common to all MCs associated with one glomerulus.

2-Amino-5-phosphonovalerate↗
PubMed2004

EGF activates intracellular and intercellular calcium signaling by distinct pathways in tumor cells.

Epidermal growth factor (EGF)-mediated Ca2+ signaling in multiple cell lines derived from human gliomas and in the A431 epidermoid carcinoma cell line was observed using fluorescence videomicroscopy. Bath application of EGF evoked an oscillatory increase in [Ca2+]i in 4 different human glioma cell lines as well as the A431 cell line. This effect was blocked by the EGF receptor tyrosine kinase inhibitors gefitinib and erlotinib, as well as by the EGFR antibody cetuximab. In addition to this acute Ca2+ signaling response, transient exposure to EGF also potentiated subsequent Ca2+ signaling responses to other stimuli. Tumor cells transiently exposed to EGF (5 minutes), showed a sustained increase in propagation of intercellular Ca2+ waves, which have been previously shown to involve release of ATP and activation of purinergic receptors. Cells transiently exposed to EGF also showed a sustained potentiation of the Ca2+ signaling response to ATP. In contrast to the acute Ca2+ signaling response to EGF, this sustained potentiation of purinergic intercellular signaling was not blocked by gefitinib or erlotinib, while it was blocked by cetuximab. These results indicate that while the acute Ca2+ signaling response requires tyrosine kinase activation, the sustained potentiation of intercellular signaling occurs via a distinct pathway. Distinct intra- and intercellular Ca2+ signaling pathways may be mechanisms by which EGF modulates the growth and migration of tumor cells.

Adenosine Triphosphate↗
PubMed1998

Na+/Ca2+ exchanger overexpression impairs calcium signaling in fibroblasts: inhibition of the [Ca2+] increase at the cell periphery and retardation of cell adhesion.

We examined the Ca2+ handling property and cell function of CCL39 fibroblasts highly overexpressing the cardiac isoform (NCX1) of Na+/ Ca2+ exchanger. In NCX1 transfectants in 146 mM Na+, ionomycin, alpha-thrombin or thapsigargin only produced a small transient increase in [Ca2+]i compared to the large increase seen in control cells, although resting [Ca2+]i was not significantly different between these cells. In Na+-free medium, in contrast, the [Ca2+]i responses in NCX1 transfectants and control cells stimulated with these agents were not different, indicating that the Ca2+ content of the intracellular store(s) does not decrease on NCX1 transfection. The expression levels of the endoplasmic reticulum and plasma membrane Ca2+-ATPases, and thrombin- or serum-stimulated cell growth were not altered in NCX1 transfectants. The latter finding suggests that Ca2+ signaling in the nucleus is not impaired appreciably. On fluorescence imaging and confocal microscopy, we found that [Ca2+] did not increase in the peripheral cytoplasm of these cells treated with alpha-thrombin in Na+-containing medium. In these NCX1 transfectants, activation of the plasma membrane Ca2+-activated K+ channels by thrombin or ionomycin was markedly suppressed, and the integrin-mediated adhesion to substrate was significantly delayed compared with control cells. NCX1-overexpressing CCL39 cells thus seem to be a good model with which we can study the Ca2+-regulated membrane processes under physiologically relevant conditions.

Animals↗
PubMedDate not supplied

Mitochondria and calcium signaling.

The kinetic properties for the uptake, storage and release of Ca2+ from isolated mitochondria accurately predict the behaviour of the organelles within the intact cell. While the steady-state cycling of Ca2+ across the inner membrane between independent uptake and efflux pathways seems at first sight to be symmetrical, the distinctive kinetics of the uniporter, which is highly dependent on external free Ca2+ concentration and the efflux pathway, whose activity is clamped over a wide range of total matrix Ca2+ by the solubility of the calcium phosphate complex provide a mechanism whereby mitochondria reversibly sequester transient elevations in cytoplasmic Ca2+. Under non-stimulated conditions, the same transport processes can regulate matrix Ca2+ concentrations and hence citric acid cycle activity.

Animals↗
PubMedDate not supplied

Neuronal and glial calcium signaling in Alzheimer's disease.

Cognitive impairment and emotional disturbances in Alzheimer's disease (AD) result from the degeneration of synapses and death of neurons in the limbic system and associated regions of the cerebral cortex. An alteration in the proteolytic processing of the amyloid precursor protein (APP) results in increased production and accumulation of amyloid beta-peptide (Abeta) in the brain. Abeta has been shown to cause synaptic dysfunction and can render neurons vulnerable to excitotoxicity and apoptosis by a mechanism involving disruption of cellular calcium homeostasis. By inducing membrane lipid peroxidation and generation of the aldehyde 4-hydroxynonenal, Abeta impairs the function of membrane ion-motive ATPases and glucose and glutamate transporters, and can enhance calcium influx through voltage-dependent and ligand-gated calcium channels. Reduced levels of a secreted form of APP which normally regulates synaptic plasticity and cell survival may also promote disruption of synaptic calcium homeostasis in AD. Some cases of inherited AD are caused by mutations in presenilins 1 and 2 which perturb endoplasmic reticulum (ER) calcium homeostasis such that greater amounts of calcium are released upon stimulation, possibly as the result of alterations in IP(3) and ryanodine receptor channels, Ca(2+)-ATPases and the ER stress protein Herp. Abnormalities in calcium regulation in astrocytes, oligodendrocytes, and microglia have also been documented in studies of experimental models of AD, suggesting contributions of these alterations to neuronal dysfunction and cell death in AD. Collectively, the available data show that perturbed cellular calcium homeostasis plays a prominent role in the pathogenesis of AD, suggesting potential benefits of preventative and therapeutic strategies that stabilize cellular calcium homeostasis.

Adenosine Triphosphate↗
PubMed2006

Calcium signals and mitochondria at fertilisation.

At fertilisation, Ca(2+) signals activate embryonic development by stimulating metabolism, exocytosis and endocytosis, cytoskeletal remodelling, meiotic resumption and recruitment of maternal RNAs. Mitochondria present in large number in eggs have long been thought to act as a relay in Ca(2+) signalling at fertilisation. However, only recently have studies on ascidians and mouse proven that sperm-triggered Ca(2+) waves are transduced into mitochondrial Ca(2+) signals that stimulate mitochondrial respiration. Mitochondrial Ca(2+) uptake can substantially buffer cytosolic Ca(2+) concentration and the concerted action of heterogeneously distributed mitochondria in the mature egg may modulate the spatiotemporal pattern of sperm-triggered Ca(2+) waves. Regulation of fertilisation Ca(2+) signals could also be achieved through mitochondrial ATP production and mitochondrial oxidant activity but these hypotheses remain to be explored. A critically poised dynamic interplay between Ca(2+) signals and mitochondrial metabolism is stimulated at fertilisation and may well determine whether the embryo can proceed further into development. The monitoring of Ca(2+) signals and mitochondrial activity during fertilisation in living zygotes of diverse species should confirm the universality of the role for sperm-triggered Ca(2+) waves in the activation of mitochondrial activity at fertilisation.

Animals↗
PubMed2002

TGF-beta1 calcium signaling increases alpha5 integrin expression in osteoblasts.

TGF-beta1 is a potent osteoactive factor and exhibits a wide variety of effects on osteoblasts, most of which are mediated through receptor associated Smad proteins. We have recently reported a novel TGF-beta1 intracellular Ca2+ signaling pathway in osteoblasts, and found that this signaling is required for the TGF-beta1 mediated enhancement of osteoblast adhesion to substrate. Given that interaction between the extracellular matrix protein fibronectin and alpha5beta1 integrin on the cell surface is principally responsible for osteoblast substrate adhesion, we examined here whether the TGF-beta1 stimulated Ca2+ signal is involved in this pathway. Our results show that, in primary human osteoblasts, the TGF-beta1 induced intracellular Ca2+ signal is responsible, in part, for the stimulation of expression of alpha5 integrin, but not of beta1 integrin or fibronectin. Increased levels of alpha5 integrin protein and mRNA were seen as early as 12 h after TGF-beta1 treatment, but were inhibited by co-treatment of cells with nifedipine, a selective L-type Ca2+ channel blocker. TGF-beta1 treatment increased both fibronectin and beta1 integrin protein production within 48 h, in a manner unaffected by co-treatment with nifedipine. Immunofluorescence observations revealed that TGF-beta1 treatment resulted in increased alpha5 integrin staining, and more prominent alpha5 integrin clustering, with increased co-localization with the actin cytoskeleton, effects that were blocked by co-treatment with nifedipine. The TGF-beta1 induced intracellular Ca2+ signal in human osteoblasts is thus an important mechanistic step in the regulation of alpha5 integrin expression, later contributing to enhanced cell adhesion.

Calcium Channel Blockers↗
PubMed1998

Vasopressin-induced calcium signaling in cultured cortical neurons.

Earlier autoradiographic studies from our laboratory detected vasopressin recognition sites in the mammalian cerebral cortex [R.E. Brinton, K.W. Gee, J.K. Wamsley, T.P. Davis, H.I. Yamamura, Regional distribution of putative vasopressin receptors in rat brain and pituitary by quantitative autoradiography, Proc. Natl. Acad. Sci. U. S.A., 81 (1984) 7248-7252; C. Chen, R.D. Brinton, T.J. Shors, R.F. Thompson, Vasopressin induction of long-lasting potentiation of synaptic transmission in the dentate gyrus, Hippocampus, 3 (1993) 193-204]. More recently, we have detected mRNA for the V1a vasopressin receptors (V1aRs) in cultured cortical neurons [R.S. Yamazaki, Q. Chen, S.S. Schreiber, R.D. Brinton, V1a Vasopressin receptor mRNA expression in cultured neurons, astroglia, and oligodendroglia of rat cerebral cortex, Mol. Brain Res., 45 (1996) 138-140]. To determine whether these recognition sites are functional receptors, we have pursued the signal transduction mechanism associated with the V1a vasopressin receptor in enriched cultures of cortical neurons. Results of these studies demonstrate that exposure of cortical neurons to the selective V1 vasopressin receptor agonist, [Phe2,Orn8]-vasotocin, (V1 agonist) induced a significant accumulation of [3H]inositol-1-phosphate ([3H]IP1). V1 agonist-induced accumulation of [3H]IP1 was concentration dependent and exhibited a linear dose response curve. Time course analysis of V1 agonist-induced accumulation of [3H]IP1 revealed a significant increase by 20 min which then decreased gradually over the remaining 60 min observation period. V1 agonist-induced accumulation of [3H]IP1 was blocked by a selective V1a vasopressin receptor antagonist, (Phenylac1, D-Tyr(Me)2, Arg6,8, Lys-NH29)-vasopressin. Results of calcium fluorometry studies indicated that V1 agonist exposure induced a marked and sustained rise in intracellular calcium which was abolished in the absence of extracellular calcium. The loss of the rise in intracellular calcium was not due to a failure to induce PIP2 hydrolysis since activation of the phosphatidylinositol pathway occurred in the absence of extracellular calcium. V1 agonist activation of calcium influx was then investigated. V1 agonist-induced 45Ca2+ uptake was concentration dependent with a biphasic time course at 250 nM. Preincubation with the L-type calcium channel blocker, nifedipine, blocked V1 agonist-induced calcium influx suggesting V1 agonist-induced L-type calcium channel activation in cortical neurons. Furthermore, V1 agonist-induced calcium influx was blocked by both bisindolyleimide I (PKC inhibitor) and U-73122 (PLC inhibitor) suggesting a modulation of V1 agonist-induced L-type calcium channel activation by downstream components of the phosphatidylinositol signaling pathway such as protein kinase C. These results indicate that in cultured cortical neurons, V1a vasopressin receptor activation leads to induction of the phosphatidylinositol signaling pathway, influx of extracellular calcium via L-type calcium channel activation, and a rise in intracellular calcium which is dependent on V1a receptor activated influx of extracellular calcium. These data are the first to demonstrate an effector mechanism for the V1 vasopressin receptor in the cerebral cortex and provide a potential biochemical mechanism that may underlie vasopressin enhancement of memory function.

Animals↗
PubMed2005

Involvement of phospholipase C and intracellular calcium signaling in the gonadotropin-releasing hormone regulation of prolactin release from lactotrophs of tilapia (Oreochromis mossambicus).

Gonadotropin-releasing hormone (GnRH) is a potent stimulator of prolactin (PRL) secretion in various vertebrates including the tilapia, Oreochromis mossambicus. The mechanism by which GnRH regulates lactotroph cell function is poorly understood. Using the advantageous characteristics of the teleost pituitary gland from which a nearly pure population of PRL cells can be isolated, we examined whether GnRH might stimulate PRL release through an increase in phospholipase C (PLC), inositol triphosphate (IP3), and intracellular calcium (Ca(i)2+) signaling. Using Ca(i)2+ imaging and the calcium-sensitive dye fura-2, we found that chicken GnRH-II (cGnRH-II) induced a rapid dose-dependent increase in Ca(i)2+ in dispersed tilapia lactotrophs. The Ca(i)2+ signal was abolished by U-73122, an inhibitor of PLC-dependent phosphoinositide hydrolysis. Correspondingly, cGnRH-II-induced tPRL188 secretion was inhibited by U-73122, suggesting that activation of PLC mediates cGnRH-II's stimulatory effect on PRL secretion. Pretreatment with 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate hydrochloride (TMB-8), an inhibitor of Ca2+ release from intracellular stores, impeded the effect of cGnRH-II on Ca(i)2+. To further address the possible involvement of intracellular Ca2+ stores, IP3 concentrations in the tilapia rostral pars distalis (RPD containing 95-99% PRL cells) was determined by a radioreceptor assay. We found that GnRH-II induces a rapid (<5min) and sustained increase in IP3 concentration in the RPD. Secretion of tPRL(188) in response to cGnRH-II was suppressed by Ca2+ antagonists (TMB-8 and nifedipine). These data, along with our previous findings that show PRL release increases with a rise in Ca(i)2+, suggest that GnRH may elicit its PRL releasing effect by increasing Ca(i)2+. Furthermore, the rise in Ca(i)2+ may be derived from PLC/IP3-induced mobilization of Ca2+ from intracellular stores along with influx through L-type voltage-gated Ca2+ channels.

Animals↗
PubMed2003

Calcium signalling: NAADP comes out of the shadows.

The molecular mechanisms through which extracellular stimuli mobilize intracellular Ca(2+) stores are still incompletely understood. Recent work suggests that nicotinic acid-adenine dinucleotide phosphate (NAADP) can finally join the ranks of genuine Ca(2+)-mobilizing second messengers.

Animals↗